FR2557098A1 - PROCESS FOR THE PREPARATION OF SUBSTITUTED HYDROXY AND / OR ALKOXY BROMOBENZALDEHYDES - Google Patents

Abstract

Substituted bromobenzaldehydes, e.g., 5-bromovanillin, are facilely prepared with overall avoidance of HBr by-product, by (i) first brominating the corresponding benzaldehyde with a less than stoichiometric amount of bromine, and (ii) completing said bromination reaction with a brominating couple which comprises (1) the hydrobromic acid generated in situ in the step (i) and (2) a bromide ion oxidizer.

Description

PRECEDING PREPARATION OF BROMBENZALHYDSES HYDROXY AND / CJ

ALKOXY SUBSTITUES

  The present invention relates to a process for the preparation of bromobenzaldehydes having hydroxy and / or alkoxy substituents and

  more particularly bramo-5 vanillin.

  Bromobenzaldehydes having hydroxy and / or alkoxy substituents are valuable industrial products used as intermediates in organic synthesis. Thus bromo-5-vanillin (3-bromo-4-hydroxy-methoxy-benzaldehyde), bromoprotocatechic aldehyde (bromo-3-dihydroxy-4,5-benzaldehyde) and bromo-3-dimethoxy-4,5-benzaldehyde are used as intermediates for the preparation 3,4,5-trimethoxybenzaldehyde which itself is involved in the manufacture of pharmaceutical products such as trimethoprim [2,4-diamino-3,4,5-trimethoxybenzyl] -5-pyrimidine]. These bromobenzaldehydes are also used for the preparation of bromncphnylalanines having

  an activity as hypotensive (see French Patent 1,592,518).

  The alkoxy and / or substituted hydroxy bromcbenzaldehydes are

  prepared by reacting bromine with the corresponding aldehyde.

  Various methods of bromination of aromatic aldehydes are known. Thus, it has been proposed to carry out the bromination of the hydroxy and / or alkoxybenzaldehydes in various reaction media. The most commonly used solvent is glacial acetic acid optionally containing an alkaline acetate such as sodium acetate, cf. DAKIN, Am. Chem. Journal 42 477-98 (1909); TORREY et al., J. Am. Chem. Soc. 31583-585 (1909); O.S.BRADY et al., J. Chem. Soc. 107, 1858-62 (1915); E.I.SHRINER et al., J. Am. Chem. Soc. 2194 (1929); R. A. Mc IVOR et al., Cand. J. of Chem. 32, 298-302 (1953); HERY et al., J. Chem. Soc. (1930)

  2279-89; F. MISANI et al, J. Org. Chem. 356 (1945); R. PSCHORR Pnn.

  391 23-39 (1912); French patent 1,592,518. Although this process leads to excellent yields of bromobenzaldehydes, especially in the case of vanillin, it suffers from various disadvantages which makes it unattractive industrially. In particular, this process leads at the end of the reaction to a solution of hydrobromic acid in acetic acid from which it is difficult, if not practically impossible, to

recover HBr.

  It has also been proposed (see R. PSCHORR lcc cit.) To replace the glacial acetic acid with chloroform; in this case it is difficult to rid bromobenzaldehyde hydrobromic acid it contains by washing with chloroform which involves the use of a third washing solvent and makes the complex process to implement industrially. In French Patent 72 / 38,410, published under No. 2,177,693, there has been described a process for bromination of vanillin by adding a solution of vanillin in hydrobromic acid at 48% by weight.

weight of HBr to bromine.

  Lower alcohols, and especially ethanol, have also been used as brominating medium (see F. TIEMAN et al., Ber 7,615 [1874]). Joint formation of irrecoverable methyl bromide or ethyl bromide which may be difficult to valorize in the context of a large production of bromovanillin makes this process unattractive. In all cases, the reaction results in the formation of a hydrochloric acid molecule per molecule of bromobenzaldehydes produced in accordance with the following reaction scheme.

GOLD GOLD

* | OR 'OR'

a) Q + Br2 - Br "

CHO CHO

  It can be seen that in such a process only half of the bromine involved is used for the formation of bromobenzaldehydes, the other half producing hydrobromic acid or, depending on the solvent used, alkyl bromides. The recovery and / or the valorization of these by-products diminish the industrial interest of this process whatever

its mode of implementation.

  Thus, it follows from this analysis of the state of the art that the joint formation of HBr resulting from the use of the slab as a brominating agent poses a problem for the industrial implementation of

known methods.

  The present invention specifically aims to solve the problem posed by the formation of hydrobromic acid generated during

of the bromination reaction.

  More specifically, the present invention relates to a process for the preparation of substituted bromobenzaldehydes of the general formula:

Br-4--

  CHO in which R and R ', identical or different, represent a hydrogen atom or a methyl or ethyl radical by reaction of a general formula aldehyde: OR OR'

(I)

  CHO with bromine, characterized in that one cperes with a bromine amount lower than the stoechiometry of the reaction and that the bromination reaction is carried out by the intervention of the couple constituted by the hydrogen bromide generated in the reaction and an oxidizing agent bromide ions. As the oxidizing agent of the bromide ions, any chemical compound known to have this property can be used. In particular, hydrogen peroxide, nitric acid,

  hypochlorites, especially in the form of alkaline hypochlorites.

  Although it is generally known to oxidize bromide ions to bromine with the aid of certain oxidants, the use of the HBr / oxidant pair to carry out the bromination of the hydroxy and / or alkoxy benzaldehydes could lead to the fear of oxidation and / or substitution reactions of the starting material. Thus, the prior art teaches the oxidation by hydrogen peroxide of the aldehyde group according to a reaction of the Baeyer and Williger type (see CH HASSAL, Organic Reactions, Wvlume 9 pages 73 to 106 [1957], JE LEFFIER, Chem Rev 45 pages 385 to 410 [1949]). The solution of the problem posed by the bramnation of hydroxy and / or substituted alkoxy aromatic aldehydes was therefore not necessary.

obvious way.

  Without limiting in any way the invention to a particular mechanism, it can be considered that the bramation process proposed above implements the following reactions: a) partial bramation of the aldehyde by a brnoma defect according to the scheme

GOLD GOLD

  I OR 'a OR' OR i) 2 SQ + Br2> Br Q9 + O + HBr

I +

CHO CHO CHO

  b) bramatian of the aldehyde not converted by the HBr / oxidant pair; Thus, in the case where the latter is hydrogen peroxide, the reaction can be represented by the scheme:

GOLD GOLD

OR 'OR'

/ (HBr Eh + HA o B +2 H20

CHO CHO

  The overall balance of the reaction can then be represented by the diagram

GOLD GOLD

| OR '| GOLD'

Br Io '2 + Br2 + H202 -> 2 + 2 H20

I

CHO CHO

  The method according to the invention thus makes it possible to brominate the benzaldehydes substituted by bromine and to recover directly from the

  bromination bromine present in the hydrobromic acid produced.

  Although the bromination according to the invention can be carried out in water and / or an inert organic solvent which is preferably immiscible with water, such as halogenated aliphatic hydrocarbons or ethers, it is preferable, in order to obtain the conversion rates. and the highest yields of operating in the presence of an aliphatic or inorganic acid inert to bromine or oxidant. In this case the amount of acid expressed in molar equivalent per mole of benzaldehyde is preferably at least equal to 0.001 equivalents per mole of benzaldehyde and more particularly to 0.01 equivalents per mole of benzaldehyde. There is no critical upper limit of the amount of acid, this one

  which may constitute the reaction medium.

  According to a first variant, the process according to the invention is carried out in an alkanoic acid comprising from 2 to 7 carbon atoms such as acetic, propionic, butyric, n-pentanoic and n-hexanoic acids. Acetic acid is preferably used in which the starting benzaldehydes are soluble and which may constitute the reaction medium. It is possible to use indifferently an aqueous solution of acid whose concentration is not critical or a

anhydrous acid.

  According to a second variant, the process is carried out in the presence of a mineral acid which may also constitute at least partially the reaction medium. It is preferred to use aqueous solutions of hydrobromic and sulfuric acids whose concentration is not critical and may vary within wide limits. Thus, aqueous solutions of sulfuric acid containing from 5 to 65% by weight of H 2 SO 4 or aqueous hydrobromic acid solutions containing from 5 to 60% by weight of HBr can be used. In the latter case, solutions containing 45 to 55% by weight of HBr are preferably used because

  solubility of the starting aldehydes increases with the concentration of HBr.

  Selcn a preferred embodiment of the invention the aqueous solution

  of mineral acid constitutes at least partially the reactionary medium.

  Thus one can proceed to broaation on a suspension of benzaldehyde in an aqueous solution of H2SO4 or HBr or a solution of benzaldehydes in a concentrated solution of HBr. It is also possible to use, together with the acidic aqueous solution, an organic solvent of benzaldehyde and bromine, which is inert under the reaction conditions and preferably immiscible with water; an organic phase containing benzaldehyde is then brought into contact with an acidic aqueous phase in which the bromide ions are oxidized. This is a preferred embodiment of the method according to the invention. The variant which consists in using an aqueous solution of hydrobromic acid and an organic solvent is particularly suitable for carrying out the process. Among the solvents which are suitable for carrying out this embodiment, mention may be made of halogenated hydrocarbons (methylene chloride, chloroform, carbon tetrachloride), aliphatic ethers (isopropyl ether, amyl oxide, butyl ether). and ethyl, t-butyl ether and ethyl, n-butyl oxide,

  n-propyl, n-butyl methyl ether).

  The concentration of the starting aromatic aldehyde in the selected reaction medium is not critical and may vary within wide limits. It depends mainly on practical considerations such as the agitability of the reaction mass and the

process productivity.

  Although the amount of slab used in the process according to the invention, expressed in moles per mole of aldehyde, may vary somewhat provided that it remains below the stoichiometric amount resulting from scheme a), it is preferable that this quantity remains close to half the stoichiometric amount if it is desired to avoid or limit as much as possible the loss of bromine in the form of hydrobromic acid. Thus, the amount of bromine can be from

  preferably between 0.45 and 0.65 moles of bromine per mole of benzaldehyde.

  Of course, one would not depart from the scope of the present invention by going out of the limits of this interval. The use of an amount of bromine of less than 0.45 mole per mole of benzaldehyde, however, would result in an incomplete transformation of the starting material, and the use of an amount of bromine greater than 0.65 mole per mole of aldehyde would increase the formation of hydroformic acid not recoverable bromination. It is preferably carried out with from 0.5 to 0.6

  mole of bromine per mole of benzaldehyde.

  The amount of oxidizing agent used obviously depends on the amount of bromine used and the nature of the oxidant. It is preferable that it is in any case sufficient to ensure the complementary bromination of the benzaldehyde formed by the hydrobromic acid produced. The amount of oxidant will subsequently be expressed in moles per mole of bromine since the amount of hydrobromic acid formed depends on the amount of

bromine implementation.

  When the oxidizing agent is hydrogen peroxide the amount of 202 is preferably close to the stoichiometric amount illustrated by the reaction scheme iii), that is to say close to 1 mole per mole of bromine. We could deviate a little from this quantity

  without departing from the scope of the present invention.

  In practice this amount is preferably between 0.8 and 1.2 moles per mole of bromine and depends to some extent on the nature of the reaction medium and the acid used. When an aqueous solution of hydrobromic acid is used as the acid, a slight excess of hydrogen peroxide can be used. In other cases, it is preferable not to exceed 1 mole of 1202 per mole of bromine and even to operate with a

slight defect of oxygenated water.

  The concentration of the aqueous H 2 O 2 solution used is not critical. His choice is dictated by practical considerations familiar to those skilled in the art (eg concern not to increase the volume of the reaction mass). In general this

  concentration can range from 20 to 90% by weight of H2 2.

  When using an alkaline hypochlorite as an oxidant, the bromination reaction of excess benzaldehyde by the HBr / hypochlorite pair can be represented by the scheme:

GOLD GOLD

OR 'OR'

  iv) Br Br 2 + Br 2 + 2+ MC1 2 MC1 + 2H20

CHO CHO

  in which M represents an alkali metal. In this case the amount of hypochlorite is also preferably close to the stoichiometry of the reaction, that is to say 1 mole per mole of bromine. In practice, amounts of hypochlorite ranging from 0.7 to 1.1 moles per mole of bromine and preferably from 0.7 to 1 mole per mole of bromine are used. The

  concentration of aqueous solutions of hypochlorite is not critical.

  When nitric acid is used as an oxidant, the reaction is represented by the following scheme:

GOLD GOLD

OR 'OR

  6 a! + 3Br2 + 2HN03 - 6 Br + 4 H20 + 2 ND

I I

CHO CHO

  The amount of nitric acid used to ensure the oxidation of the bromide brane is preferably close to the stoichiometry of the reaction represented by scheme v) that is to say close to 2/3 of a mol of HNO 3 for 1 mole of Br2. We can, however, deviate substantially

  stoichiometry without departing from the scope of the invention.

  Thus the amount of nitric acid can vary within a range of 0.3 to 0.8 moles of HNO 3 per mole of bromine or

  preferably from 0.6 to 0.7 moles of HNO3 per mole of bromine.

  The concentration of the aqueous nitric acid solution used to complete the bromination is not critical and may be between 20 and 90% by weight of HNO 3. However, it is advantageous to use concentrated solutions so as not to increase the volume of the reaction mass. Solutions containing from 55 to 70% by weight of

HNO3 are well suited.

  It has been found advantageous to use in conjunction with nitric acid a small amount of nitrous acid which provides a rapid start of the reaction. In this case, an alkaline nitrite (NaNO 2, KNO 2) is used as the initiator. An amount of the order of 0.01 mole of nitrite per mole of aldehyde is sufficient to initiate the reaction; in general it is not necessary to use more than 0.2 moles of nitrite per mole of benzaldehyde; amounts between 0.05

  and 0.15 moles of nitrite per mole of benzaldehyde are suitable.

  The temperature at which the bromination reaction is conducted

  may be between 0 and 1000C and preferably between 5 and 60 C.

  Among the aldehydes of formula (I) which can be brominated by the process of the invention, mention may be made of protocatechic aldehyde (3,4-dihydroxybenzaldehyde), vanillin and ethyl vanillin,

  isovanillin and veratric aldehyde (3,4-dimethoxy benzaldehyde).

  Protocatechic aldehyde, vanillin and ethylvanillin lead to bromobenzaldehydes having a bromine atom in the meta position relative to the aldehyde group. The veratric aldehyde leads to 2-bromo-4-hydroxy-3-methoxybenzaldehyde and isovanillin to bromo-2-methoxy-4-hydroxy-5-benzaldehyde). The process according to the invention is suitable

  especially well to the bromination of vanillin to bromo-5-vanillin.

  The present method is particularly suitable for use in

continuous work.

  The following examples illustrate the invention and show how

it can be put into practice.

EXAMPLE 1

  In a 100 ml glass flask equipped with a stirring system, a thermometer, a dropping funnel and cooled with a 20 C water bath, 20 ml of anhydrous acetic acid are charged and then 7.5 g of vanillin (0.05 mol). The stirring is started then, when the vanillin is dissolved, a solution of 4.8 g of braome (0.03 mol) in 10 ml of acetic acid is added dropwise. The temperature rises progressively to 30 ° C. When the addition of the slab is completed, ml of acetic acid is added, followed by dropwise 2.26 g of acygenated water% H 2 O 2 (0.02 mol). Stirring is maintained for 10 minutes after the end of the casting and the heterogeneous reaction mass is cooled to 20 ° C. It is filtered and the cake is washed on filter with 10 ml of fresh acetic acid and then with 30 ml of ice water. After drying under vacuum, 10.8 g of a product melting at 162 ° C., in which 10.60 g of 5-bromo-5-methylvillin were determined by high pressure liquid chromatography, were collected. 0.45 g of vanillin are added to the filtrate and the acetic acid washing.

not transformed.

  The conversion rate of vanillin was 94% and the yield of bracmo-5 vanillin compared to vanillin converted to 98%.

EXEMPLES 2 to 3

  The procedure is as in Example 1 in 50 ml of acetic acid and using the following vanillin / bram / F 02 molar ratios: EXAMPLE: vanillin: Br 2 2 T (1) R (2)

2 H202 TI (1): RT (2):

:: (moles): mole: mole%

: :::::

: 2: 2: 1: 1.04: 96.6: 90:

: ": ':: * ::'

: 3: 2: 1 ,: 1: 92,6: 92,7:

:::::::

:. :: :: ': 2

  (1) conversion rate of vanillin

  (2) yield of bromovanillin relative to transformed vanillin.

EXAMPLE 4

  250 ml of a 2N aqueous solution of sulfuric acid and then 15.15 g of vanillin (0.1 mol) are charged into a 250 ml flask equipped as in Example 1. The stirring is started, and then 9.6 g (0.6 mole) of bromine dropwise are added to the vanillin suspension. the temperature rises gradually to 30 ° C. When the addition is complete, 4.42 g of an aqueous solution containing 30.8% by weight of H 2 O 2 (ie 0.04 mol) are cast in the same manner. After the end of the casting is maintained 5 minutes stirring. The heterogeneous residue-containing mass is cooled to 20 ° C., and the solid phase is separated by filtration, washed on a filter with water and then dried at 60 ° C. under reduced pressure. The filtrate is extracted 3 times with 150 ml of methylene chloride. Unconverted vanillin and bromovanillin in the solid phase and in the methylene chloride wash were used.

  liquid chromatography under high pressure.

  In this way, 2.92 g of vanillin (ie a degree of conversion of 80.7%) and 16.42 g of bromo-5-vanillin (0.071 mol) are determined, which corresponds to a theoretical yield of 88.1%. compared to the

transformed vanillin.

EXAMPLE 5

  In the apparatus of Example 4, 110 ml of chloroform were charged and then 15.15 g of vanillin and stirring was started. When the vanillin is dissolved, 20 ml of a 2N aqueous solution of H 2 SO 4 are added. 9.6 g of bromine (0.06 mol) are then introduced dropwise into the resulting scavenger mass. The temperature is gradually raised to 30 ° C. When the addition of the bromine is completed, the feedstock in the same manner is 4.42 g of an aqueous solution containing 30% by weight of H 2 O 2 (ie 0.04 mol). Bromo-5 vanillin which has precipitated as it is formed is separated by filtration The liquid phases of the filtrate are separated by decantation and the aqueous phase is extracted

  3 times per 150 ml of methylene chloride each time.

  Using the same method as in the previous examples, a total of 1.21 g of unprocessed vanillin (a conversion rate of 92%) and 21.07 g of 5-bromo-5-vanillin were assayed.

  represents a yield of 99.5% compared to transtoeme vanillin.

EXAMPLE 6

  The procedure was carried out under the same conditions as in Example 5, replacing the sulfuric acid with 50 ml of an aqueous solution of acid.

  hydrobromic, the volume of chloroform being 100 ml.

  Under these conditions, the conversion rate of lauloe was 94.84% and the yield of bromo-5 vanillin compared to

transformed vanillin 96.4%.

EXAMPLE 7

  We operated as in example 6 but using a report

  molar mvanillin / brcme / H202 equal to 2/1 / 1.1.

  In these conditions the degree of conversion of% dline was 95.5% and the yield of bromo-5 vanillin compared to

transformed vanillin 98.1%.

EXAMPLE 8

  The procedure was as in Example 7, replacing the acid

  2N hydrobromic solution with 40 ml of a 48% by weight aqueous solution of HBr.

  Under these conditions, the degree of conversion of vanillin was 95.5% and the yield of 5-valentine bromine compared to

transformed vanillin 94.7%.

EXAMPLE 9

  Example 7 was repeated but leaving the temperature

  rise to 50 ° C at the end of the reaction.

  Under these conditions, the conversion rate of vanillin was 94.8% and the yield of 5-bromo-vanillin compared to

transformed vanillin 95.7%.

EXAMPLE 10

  Example 7 was repeated but the temperature was lowered to 0 ° C.

  Under these conditions, the degree of conversion of vanillin was 82.26% and the yield of 5-bromo-vanillin compared to

transformed vanillin 96.6%.

EXAMPLE 11

  Example 7 was repeated replacing the oxygenated water with 0.0187 moles of HNO3 (aqueous solution 65% by weight of HNO3) and 0.01

mole of sodium nitrite.

  Under these conditions, the degree of conversion of vanillin was 75.6% and the yield of 5-bromo-vanillin compared with

transformed vanillin 91.02%.

EXAMPLE 12

  Example 7 was repeated replacing hydrogen peroxide with

  0.0277 moles of NaOCl (2N aqueous solution).

  Under these conditions, the degree of conversion of vanillin was 76.8% and the yield of 5% brcmno-vanillin compared with

transformed vanillin 89.2%.

255'7098

EEM1PLE 13

  It was tested as in Example 7 but adding simultaneously

bromine and hydrogen peroxide.

  Under these conditions, the degree of conversion of vanillin was 97.4% and the yield of 5-bromo-vanillin compared to

transformed vanillin 94.1%.

EXAMPLE 14

  Example 7 was repeated after replacing chlorform with

250 ml of isoprcpyl oxide.

  Under these conditions, the degree of conversion of vanillin was 86.2% and the yield of 5-bromo-vanillin compared with

transformed vanillin 94.1%.

EXAMPLE 15

  The procedure was as in Example 7 but replacing the 2N aqueous solution of HBr with an aqueous solution of 0.5 N HBr (same volume: mi). Under these conditions, a vanillin conversion rate of 71.5% and a bromo-vanillin yield in relation to

transformed vanillin 86.2%.

EXEMPLE 16

  we operated as in example 7 but replacing the solution

aqueous HBr 2N with water alone.

  A conversion rate of vanillin of 64.2% is obtained

  and a yield of 5-bromo-vanillin relative to vanillin of 82.9%.

EXAMPLE 17

  Example 11 was repeated but introducing 0.050 mol of

  HNO3 as a 65% aqueous solution and 0.01 mole NaNO2.

  Under these conditions, a conversion rate of vanillin of 96.7% and a yield of 5-bromo-vanillin with respect to

transformed vanillin 83%.

EXAMPLE 18

  Example 13 was repeated but introducing 0.050 mole of

NaOCl (2N aqueous solution).

  Under these conditions, the conversion rate of vanillin is 81.1% and the yield of bromo-5-vanillin relative to

  transformed vanillin is 85.7%.

Claims (11)

  1) Process for the preparation of substituted bromcbenzaldehydes of general formula: OR Br + J CHO in which R and R ', which may be identical or different, represent a hydrogen atom or a methyl or ethyl radical by reacticon of an aldehyde general formula: ' 0 X (II)   CHO with bromine, characterized in that it is creped with an amount of slab less than the stoichiometry of the reaction and that the bromination reaction is completed by the intervention of the couple constituted by the hydrobromic acid generated in the reaction and an oxidizing agent of the bromide ions. 2) Process according to claim 1, characterized in that the aldehyde of formula (II) is brought into contact simultaneously with a defect of bromine and an oxidant.   3) Process according to claim 1, characterized in that the reaction is carried out in two successive stages consisting of partially brominating with the bromine a benzaldehyde of formula (II) and then to be completed.   bromination by adding an oxidant of the brominated ions.   4) Process according to any one of claims 1 to 3,   characterized in that the oxidant is selected from the group consisting of   hydrogen peroxide, nitric acid and alkaline hypochlorites.    Method according to any one of claims 1 to 4,   characterized in that the amount of bromine is between 0.45 and   0.65 moles per mole of benzaldehyde.   6) Process according to any one of claims 1 to 4,   characterized in that the amount of oxygenated water is between 0.8 and 1.2 moles per mole of bromine.   7) Process according to any one of claims 1 to 4,   characterized in that the amount of nitric acid is between 0.3   and 0.8 moles of HNO3 per mole of bromine.   8) Process according to any one of claims 1 to 5,   characterized in that the amount of hypochlorite is between 0.7 and 1.1 moles per mole of bromine.   9) Method according to any one of claims 1 to 6,   characterized in that the bromination is carried out in the presence of an acid carboxylic or mineral.    Process according to any one of claims 1 to 9, characterized in that the reaction is carried out in an alkanoic acid   liquid under the conditions of the reaction.   11) Method according to claim 10, characterized in that   the alkanoic acid is acetic acid.   12) Process according to any one of claims 1 to 9,   characterized in that the reaction is conducted in an aqueous solution of a mineral acid taken from the group consisting of sulfuric acid and hydrobromic acid.   13) Method according to any one of claims 1 to 9,   characterized in that the reaction is conducted in an inert organic solvent of benzaldehyde and bromine, immiscible with water and in the presence of an aqueous solution of a mineral acid taken from the group formed by   sulfuric acid and hydrobromic acid.   14) Process for preparing bromcbenzaldehydes of formula (I) having a bromine atom in the meta position with respect to the group   aldehyde according to one of claims 1 to 12, characterized   a aldehyde of formula (II) in which R represents a hydrogen atom and R 'an atom is used as starting aldehyde.   hydrogen or a methyl or ethyl radical.